Thursday, December 14, 2017

Sew Chaotically! - The good, the bad, and the ugly!!! The ROBE to hell is paved with good intentions!!!

If I had one shred of pride, there is NO WAY I would share the following sewing disaster!!!  However, as my biologic children, along with all the others I care for daily will readily attest - "Pride???  She has none!"  I will sing, beg, dance, pantomime hygiene name it!  Whatever it takes to impress them with good health habits and foster their self esteem, I'll do!!  At this point in my life, I ain't got time for nothing but straight talk, whether it's about melanoma, health care as a right, the well being and education of our children, the importance of standing up for the least among us, or - sewing!  If I can share information that helps someone or makes them smile - I figure I did something worthwhile.  Now....don't get your hopes too high!!!!  I don't think I am going to change the world or teach anybody anything with THIS post!!!  But, here you go....

As you may recall, I made this jacket from a very lush fleece for a friend. Sew Chaotically! - Kimono Sashiko Jacket - Lisette B6464, plus 2 in fleece!  It went together beautifully.  It was awesome.  Everyone who saw it admired its cuteness, its finished seams, the symmetry of the collar!  And, hell! It was so easy...I made 2!!!!  Flushed with my own success, I thought - "I'll make everybody fleece robes for Christmas!!!  It will be fabulous and so easy!!!"

I even had a couple of patterns (more on that later).  This one seemed the best to use for my purposes, though it was decidedly ancient having been gifted to me from a sewist's stash years ago.  I confessed my plan to Rosie who was really psyched about the prospect!  Being cold natured she really WANTED a warm fluffy robe!  (I was pretty certain the other recipients would not be that excited about a robe...but I thought they could still enjoy one.) She happily joined me at our local JoAnn's to pick out the perfect fleece for herself and others.  With her love of purple she chose a lush purple plaid and a matching solid.

HOW DID IT GO SO WRONG????  I ask you.  Have you EVER seen a sadder excuse for a garment?  Of any sort?  Oh. My. LORD!!!!  I put forth a good deal of effort here!  EVERY seam was first stitched on my machine with the appropriate needle and walking foot...then meticulously serged.  Knowing Roo was probably the only person who truly wanted a robe, I didn't really want to make hers first, but she was my tiniest person and I reasoned I could better judge how to increase the size for the others by making hers first.  And, yes...I will address the elephant in the picture.  What the hell happened with those pockets?????  I actually worked hard on their placement!  I MEASURED carefully!  Basted in place.  Laying flat they are perfect.  Hold the robe up....and there you go!

Incredibly deflated, I tackled one for the Jamester!  Rosie had picked his material carefully.  Given the bunch of mess her robe with its contrasting "neck band" had turned into, I decided to skip that business!  To heck with using the walking foot first as well.  I just sewed the sucker up on the serger and folded the neck over.  Results are only mildly better generally.  Pocket placement was intentionally skewed with a slightly better outcome.  By now...I am beyond!!!  Why the hell had I thought this was a good idea????  How is this turning out so very, extremely badly?????!!!!  I texted Roo.  "Do you like perfect pie, symmetric and pristine, as though straight from the bakery?  Or do you find you prefer the rustic variety, with the tasty, albeit cracked and somewhat broken crust...delicious and baked the love?"  She replied, "Both?  Why?"  I said, "Never mind.  You and Jamie can have your durn robes.  They are horrifying.  I'll bring them to our workout.  My only requirement is that you have to open them together and I need pics!!!"

These pics...

...have made me (and many others)....


...until we had tears....

...and our stomachs hurt.  Is the Jamester a good sport or what?????

Sadly, it just gets worse!!!!  Here B is being forced to try out the robe for Fred-o who is a great deal taller, so I can try to gauge how to hem it!  However, at this point, I was getting a bit wiser....or no longer cared!  Note there is only one pocket!  (Those suckers can't look as jacked if you don't have one next door to compare it to!!!) And, I had adopted serged edges as a finished seam!!!
Wizard wand, anyone????

The fun and games that is this disaster, continued.  Here I'm trying to get my crazy model (I mean love of my life) to help me decide about sizing for a taller person with boobage!

As you might imagine ~ his 'help' was of a limited nature.

By this point, my model was about as cooperative as a recalcitrant, cranky toddler in need of a nap and a cookie.  "Hold up your arms so that I can see where to hem the sleeves," I order.
"I can't, they're tired."
"Oh, Bent.  Come on, you only held them straight for two seconds!!!"
I reply.
"This is making me really hot. It's fine. I think you're done."
(Cleaning up all the fleece fuzz that covered EVERYTHING...took hours!!!!)

Clearly, thus far, I have covered the bad and the ugly.  This last IS the good, and while it did serve to restore a bit of my sewing esteem, it seems rather wrong and selfish somehow.  To struggle on to the bitter end.... 
My sweet B gave me this (picture above) for my last birthday.  Initially, on opening the package under his watchful eyes, I was simply confused.  What the - ????  It says "women's robe".... "Purl Soho" .... in a clear package labeled ... "table cover"????  Wait a minute!  B had downloaded the Purl Soho robe pattern, remembering that I had admired it.  Then, and I think this is pretty ingenious, bought one of those thick paper table "cloths" on which to create the ensconced within the original plastic bag!!!   How sweet is that???  Perhaps I should have used this pattern all along, but he had drawn out only the small size (which would have worked for Rosie) but I wasn't certain it would work out very well with the thick fleece.

Anyhow, I made this rather lovely robe for.....ME!!!!!

The pattern is very simple with some ingenious little tricks including a hanging loop. Insides are finished with both French and flat felled seams.  The material is a super soft flannel B picked up and some remnants of a woven cotton I had left over from another project.  Both were very easy to work with.  Some folks complained of limited space in the underarm area.  I had no problems and just made the pattern as is.  However, there is a gusset piece that you can download as an addition, by Purl Soho, if you think it will be an issue for you.

I really love it!  Still, it seems super wrong to make crappy crap for others and something really nice for yourself!!!

Those smiles though!!!!!  They make my "robe to hell" totally worth it!!!  (Sorry Fred and Irina!!  I tried, I really did!!!!)
Merry Christmas, guys!!!!  Sew chaotically!  (As though I know any other way!!!) - ;>) les

Tuesday, December 12, 2017

A simple blood draw to measure serum protein - predicts outcome for melanoma patients treated with anti-PD-1????

So this is interesting:

A Serum Protein Signature Associated with Outcome After Anti-PD1 Therapy in Metastatic Melanoma. Sznol, Sullivan, Blackmon...Ascierto...Weber.  Cancer Immunol Res. 2017 Dec 5.

A mass spectrometry analysis was performed using serum from patients receiving checkpoint inhibitors to define baseline protein signatures associated with outcome in metastatic melanoma. Pre-treatment serum was obtained from a development set of 119 melanoma patients on a trial of nivolumab with or without a multi-peptide vaccine and from patients receiving pembrolizumab, nivolumab, ipilimumab, or both nivolumab and ipilimumab. Spectra were obtained using matrix assisted laser desorption/ionization time of flight mass spectrometry. These data combined with clinical data identified patients with better or worse outcomes. The test was applied to five independent patient cohorts treated with checkpoint inhibitors and its biology investigated using enrichment analyses. A signature consisting of 209 proteins or peptides was associated with progression-free and overall survival in a multivariate analysis. Test performance across validation cohorts was consistent with the development set results. A pooled analysis, stratified by set, demonstrated a significantly better overall survival for 'sensitive' relative to 'resistant' patients. The test was associated with survival in a cohort of ipilimumab-treated patients. Test classification was associated with acute phase reactant, complement and wound healing pathways. We conclude that a pre-treatment signature of proteins, defined by mass spectrometry analysis and machine learning, predicted survival in patients receiving PD-1 blocking antibodies. This signature of proteins was associated with acute phase reactants and elements of wound healing and the complement cascade. This signature merits further study to determine if it identifies patients who would benefit from PD-1 blockade.

In line with my last post....researchers keep looking for a biomarker via a simple blood draw that will predict response to a particular treatment, indicate tumor burden, note disease progression or regression, etc.  Here, researchers looked at proteins in the blood of 119 "melanoma patients on a trial of nivo with or without multi-peptide vaccine and from patients [in other immunotherapy studies]". 

Hmmmm.....anybody know ratties who took nivo with peptide vaccines???????  C'est moi!!! Results from the 33 ratties in my Nivolumb/Opdivo trial...published!  Damn!!!  The places my blood has gone with nobody telling me NOTHING about it!!!!!!!!!!!!!!!!!

ANYWAY!!!!!  In this report, researchers found that a certain set of proteins, found in the blood of patients with melanoma BEFORE treatment, "predicted survival in patients receiving PD-1 blocking antibodies."

This could be very important for folks making a decision about what treatment is best for them.  Melanoma is not kind to those who waste time.  A way to know which treatment to spend your time taking could be life saving.

Wonder what THIS rattie's proteins showed?  Seriously, how is it that clinical trials use ratties and fail to  inform them of the results of their OWN tests?  How is this okay?  WHY wouldn't you let the folks who put their lives, dollars, families, blood, protein, EVERYTHING on the line - yes, for themselves...but also for the reputations (and CV's) of researchers and facilities as well as the monetary/stock value of Big Pharma - the results determined from their literal blood, sweat and tears?  Just asking!  Sadly....not expecting answers.  Can only hope that these results will benefit melanoma peeps in the future!!!  - c

Saturday, December 9, 2017

Measuring cell-free DNA in melanoma patient's blood to determine tumor burden and prognosis

I have spent years yelling about finding a reasonable marker through a simple blood draw to determine disease burden, response to therapy, and prognosis for melanoma patients.  Here's a zillion reports - Markers for melanoma- looking at utilizing everything from progression on scans, t-cell exhaustion, lymphocytes, circulating CD8 and CD4 t cells, eosinophils, LDH, melanoma antigens, to circulating tumor cells to determine the status of a melanoma patient's disease burden.

On the topic of circulating tumor DNA alone there are these:  Circulating tumor DNA in melanoma
It can be used to determine level of disease, progression, BRAF status and response to treatment.
Now there's this:

Plasma total cell-free DNA (cfDNA) is a surrogate biomarker for tumour burden and a prognostic biomarker for survival in metastatic melanoma patients. Valpione, Gremel, Mundra, et al.  Eur J Cancer. 2017 Nov 23.

Tumour burden is a prognostic biomarker in metastatic melanoma. However, tumour burden is difficult to measure and there are currently no reliable surrogate biomarkers to easily and reliably determine it. The aim of this study was to assess the potential of plasma total cell free DNA as biomarker of tumour burden and prognosis in metastatic melanoma patients.

A prospective biomarker cohort study for total plasma circulating cell-free DNA (cfDNA) concentration was performed in 43 metastatic melanoma patients. For 38 patients, paired blood collections and scan assessments were available before treatment and at first response evaluation. Tumour burden was calculated as the sum of volumes from three-dimensional radiological measurements of all metastatic lesions in individual patients.

Baseline cfDNA concentration correlated with pre-treatment tumour burden. Baseline cfDNA levels correlated significantly with hazard of death and overall survival, and a cut off value of 89 pg/μl identified two distinct prognostic groups. Patients with cfDNA greater than/= to 89 pg/μl had shorter OS (10.0 versus 22.7 months) and the significance was maintained when compared with lactic dehydrogenase (LDH) in a multivariate analysis. We also found a correlation between the changes of cfDNA and treatment-related changes in tumour burden. In addition, the ratio between baseline cfDNA and tumour burden was prognostic.

We have demonstrated that cfDNA is a surrogate marker of tumour burden in metastatic melanoma patients, and that it is prognostic for overall survival.

These tests work!  It is time to make them a reality for those with melanoma! - c

Thursday, December 7, 2017

Pembro for mucosal melanoma vs response rate to nivo alone vs the ipi/nivo combo

A diagnosis of melanoma is bad enough.  Unfortunately, folks with mucosal melanoma have an even more difficult time.  Here's a review of two articles:

This report (Jan 2017):  Evaluation of response to nivo or ipi/nivo in Cutaneous and Mucosal Melanoma  Notes ~  889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months and 6.2 months for mucosal and cutaneous melanoma, with objective response rates of 23.3% and 40.9%, respectively. Median progression-free survival in patients treated with nivolumab combined with ipilimumab was 5.9 months and 11.7 months for mucosal and cutaneous melanoma, with objective response rates of 37.1% and 60.4%, respectively. 

Efficacy of pembrolizumab (pembro) in patients (pts) with advanced mucosal melanoma (mucMEL): data from KEYNOTE-001, 002, and 006. Hamid, Ribas, Hodi, et al.  Society for Melanoma Research 2016 Congress.  Published 29 January 2017. 

Pembro has demonstrated efficacy and a manageable safety profile in advanced MEL. We assessed outcomes of pts with advanced mucMEL enrolled in KEYNOTE-001 (NCT01295827), KEYNOTE-002 (NCT01704287), and KEYNOTE-006 (NCT01866319). Pts received pembro 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg Q2W. Response was assessed per RECIST v1.1 by independent central review. Of the 1567 pts in the pembro arms who received greater than/= to 1 pembro dose, 84 (5%) had mucMEL. 57% of pembro-treated pts with mucMEL were women, 49% were aged greater than/= to 65 y, 32% had ECOG PS 1, 48% had elevated LDH, 8% had BRAFV600 mutant tumors, 81% had M1c disease, 58% had baseline tumor size greater than/= to 77.7 mm (ie, median in total population), and 70% with known PD-L1 status had PD-L1–positive tumors. 90% of pts received greater than/= to1 prior therapy: 37% received 1, 45% received 2, and 8% received greater than/= to 3; 39% received prior ipilimumab (ipi). In pts with mucMEL, ORR was 19%, DCR was 31%, median PFS was 2.8 months, and median OS was 11.3 months. In the 16 responders, median time to response was 12.4 weeks (range, 11.1–84.1), 12 (75%) were alive without subsequent progression, and median response duration was 27.6 months (range 1.1+ to 27.6). In ipi pretreated pts with mucMEL, ORR was 15%, DCR was 27%, 4 of 5 (80%) responders were alive and without subsequent progression, and median response duration was 27.6 months. In the 1483 pembro-treated pts with non-mucMEL, ORR was 33%, DCR was 47%, median time to response was 12.4 weeks (range 3.7–144.0), 72% of responders were alive and progression free, median response duration was NR (range 1.3+ to 38.8+), median PFS was 4.2 months, and median OS was 23.5 months. Pembro is active in advanced mucMEL and provides durable activity regardless of prior ipi.

So...according to these studies:  Folks with mucosal melanoma who were given nivo alone had an objective response rate of 23% (cutaneous melanoma = 40%).  Those with mucosal melanoma given the ipi/nivo combo had a 37% objective response rate (cutaneous = 60%).  With pembro,  folks with mucosal mel not previously treated with ipi the ORR was 19%.  Those with prior ipi had a response rate of 15% to pembro.  (Generally the ORR of patients with cutaneous mel treated with pembro was 33%.)

In the end, folks with cutaneous melanoma can respond to nivo (Opdivo) or pembro (Keytruda) alone (and those responses can be durable).  However, it seems the response rate to the ipi/nivo combo is much better...though none of the response rates are as high as those that can be attained for cutaneous melanoma patients.  Hang in there, ratties.  Wishing you all my best. - c

Monday, December 4, 2017

Sew Chaotically! - Exercise tops for Roo - M7610

Or....waste not want not!  Or...playtime!!  Or...tops that are a party in the back!!! - could all serve as appropriate titles for this post.  As I've mentioned, Rosie and I are getting fit (read - having our booties kicked!!!) in a weekly Barre Boot-camp exercise class.   Rosie has always been a hardcore runner, spoiling me with workout/running/hiking tops as gifts, but pretty much just going with a jog bra and tank/tee for her own workouts.  With our new gig being downtown and all...I thought it would be fun to make her a couple of things.  And what with having recently made some knit tops...there were odd bits and bobs of left overs lying about!!!

I picked up this pattern when it was on sale and thought it would give me some perfect options.
I had this bit of underwhelming grey stretch knit, previously used as a dress lining, at hand.
However, it seemed the perfect foil for my last bit of Pinky Pink Power Woman  fabric!  Sure enough, at our last class, the combo cast its spell!  As Roo powered through her workout, a fellow classmate said, "Rose, I love your top!  It's so cute.  Where did you get it?"  Are those not the perfect words to warm a sewist's heart????
With this remnant of the super soft knit I used in my Basic InstincT Tee....
...I made this!!  The pattern has you make a twist...but that turns out rather wonky.  I tried a double twist...and a knot.  In the end, I settled on a folded gather, stitched in place.  Both are a size 12.  I folded under under a hem on the neck, arms, and bottom, but left a simple serged edge as the finish for the grey pieces front and back necklines.  My only adjustment was to scoop out the neck on both tops just a bit.  When I make them again, Rosie requests that they be a tad longer.
These were fun easy makes!  Now "sit down in your favorite chair" my real live Pinky Pink Power Woman!!! - love, mommy

Saturday, December 2, 2017

T-VEC plus ipi vs ipi alone ~ along with additional T-VEC data...

I've been posting updates about T-VEC since 2015.  Put 'T-VEC' in the search bubble and you will find a zillion articles.  Here's one from ASCO of this year, covering intralesional/intratumoral therapies generally and T-VEC in particular:  ASCO 2017: All things intralesional/intratumoral

Now there's this:

Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. Chesney, Ppuzanov, Collichio...Hamid...Lebe...Andtbacka, Kaufman.  J Clin Oncol. 2017 Oct 5.

We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. 

Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, less than/= to 4 mL × 106 plaque-forming units/mL; after 3 weeks, less than/= to 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. 

One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone( n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response. Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade greater than/= to 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Patients with the ipi/T-VEC arm certainly did better than ipi alone.  In this post: The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down -  From the interview the post covers, Dr. Weber notes:

Checkpoint Inhibition Plus Talimogene Laherparepvec
The injectable oncolytic virus talimogene laherparepvec may prove to be a much better therapeutic when paired with a checkpoint inhibitor, vs its solo use, Dr. Weber said. “If you can inject enough tumors with enough volume, I think you will begin to turn cold tumors into hot tumors, and you could follow this with checkpoint inhibition,” he explained.

The combination of ipilimumab and talimogene laherparepvec doubled the response rate over ipilimumab alone, in a study in which even patients with visceral disease (not directly injected) experienced significant responses.8 “This looks very promising. Only time will tell whether we see a very good duration of response,” he commented.

Also quite promising is the combination of talimogene laherparepvec and pembrolizumab. In the phase IB ­MASTERKEY-265 trial of 21 previously untreated patients, responses were seen in 57% of patients, including complete responses in 7 patients, with no dose-limiting toxicities.9 This regimen is now in phase III trials.

To that last point...combining T-VEC with anti-PD-1 may be even better than combining it with ipi with far fewer side effects:  T-VEC (Talimogene laherparepvec, Imlygic...whatever you want to call it) - oncolytic virotherapy may improve the efficacy of anti-PD-1 by changing the tumor microenvironment!!

One more personal report I can share ~ If you read the first report carefully, you will see that among side effects, researchers note  "chills (combination, 53%; ipilimumab alone, 3%)".  Clearly, if "chills" occur at a rate of 53% with T-VEC plus ipi and only at 3% with ipi alone...the "chills" are due to T-VEC!!!  A dear one of mine is currently taking pembro ( anti-PD-1 product) with T-VEC and tells me that he has been dealing with significant fevers.  Which of course would be the case, if a researcher reports "chills"!!!  Isn't it interesting how folks who are NOT experiencing the side effects report them??????

Thanks for sharing and being an awesome rattie, Mark!!!  Hang tough, the rest of you ratties out there!!! - c

Thursday, November 30, 2017

Safety nets and strong women.....

Yes, many men have more than helped me along my path in life and melanoma.  Dear B, Fred-o, Dr. Michaels, Dr. Weber...are just a start to the list.  Yet, there is an incredible system, an old and knowing sisterhood, that so many women, (And NO!!!  Not all women possess this wisdom...but still.....) from dear Ruthie and Rosie, to so many others near and far, neighbors and coworkers, that literally took me into their hearts and arms, giving me strength when I could not make it on my own.

Over ten years ago, I wrote this:  Women

 More recently, I recalled this post from 2011...
PPP = Pinky Pink Power Women...or... I sewed and created a new post and story ~

Sew Chaotically! - Pinky Pink M6752 and "pattern" from J Crew RTW tank!!!
Then there's the many times a wide variety of potty pics have figured largely in my world:

TB - From 2015: Happy Halloween...and then some!!!
For a better explanation read:  What to say and do....and NOT!!...for a cancer FRIEND (not patient)!

Then today...this, posted by Jeanne...brought memories flooding back and sweet tears to my eyes:

Yes, I have been carried in that net and heard those songs.  Great thanks, big hugs, much love, with laughter that makes your tummy hurt and tears flow ~ to each of you.  love, c

Wednesday, November 29, 2017

ERK inhibitor - (BVD-523) Ulixertnib. A new approach to targeted therapy for melanoma? Here's hoping!!!

Remember this crazy diagram????

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (ulixertinib). Germann, Furey, Markland, et al. Mol Cancer Ther. 2017 Sep 22.

Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF- and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic anti-proliferative effects in a BRAFV600E mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to single-agent and combination BRAF/MEK targeted therapy. Based on these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway  (NCT01781429NCT02296242 and NCT02608229).  

I like ERK!!!  I mean, I like it as I've always liked onomatopoeia!!!  (Don't you just love to say THAT word???  Onomatopoeia!!!)  I like "ERK!!!" like I like "BAM!!" in comics.  Or "tic tock" in Mother Goose and scary stories!  When I was a kid, my sisters and I played dramatic pretend games, with one of us telling the other, "Pretend like....." .  Then, the other...would indeed pretend like - whatever  - as had been prescribed for the story line.  Words like "POW!!!" and "ERK!!!" figured largely in abrupt crashes and conclusions.  So....yeah.  I like ERK!!!  Let's put the brakes on melanoma!  ERK!!!! (Thanks to the mice.  Here we go, ratties!) - love, c

Sunday, November 26, 2017

HDAC inhibitors for melanoma....what are they again????

One of my first posts about HDAC inhibitors was back in 2016:  HDAC (Histone deacetylase) inhibitors for melanoma

Noting that researchers had hopes that in melanoma they could be used to try to overcome resistance to BRAF inhibitors, though at that time...not too much had come of them.

At ASCO this year, there was this:  ASCO 2017: Pembro plus Entinostat (histone deacetylase inhibitor - HDAC)

Where as the abstract discussed combining Pembro (now Keytruda) with entinostat, I noted:  "Existing evidence supports the hypothesis that HDAC inhibitors (HDACi) may sensitize melanoma cells to immunotherapy and targeted therapy and hence bear therapeutic potential concurrent with immune checkpoint blockade or BRAF and MEK inhibition."

Now, there's this:

HDAC inhibitors enhance the immunotherapy response of melanoma cells. Booth Robers, Polkepovic, et al.  Oncotarget. 2017 May 17. eCollection 2017 Oct 10.  
We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney. Knock down of HDAC1, HDAC3, HDAC8 and HDAC10, but not HDAC6, recapitulated the effects of the HDAC inhibitors on the immunotherapy biomarkers. Using B16 mouse melanoma cells we discovered that pre-treatment with AR42 or sodium valproate enhanced the anti-tumor efficacy of an anti-PD-1 antibody and of an anti-CTLA4 antibody. In the B16 model, both AR42 and sodium valproate enhanced the anti-tumor efficacy of the multi-kinase inhibitor pazopanib. In plasma from animals exposed to [HDAC inhibitor + anti-PD-1], but not [HDAC inhibitor + anti-CTLA4], the levels of CCL2, CCL5, CXCL9 and CXCL2 were increased. The cytokine data from HDAC inhibitor plus anti-PD-1 exposed tumors correlated with increased activated T cell, M1 macrophage, neutrophil and NK cell infiltration. Collectively, our data support the use of pan-HDAC inhibitors in combination with kinase inhibitors or with checkpoint inhibitor antibodies as novel melanoma therapeutic strategies.
Here's hoping...again. - c

Saturday, November 25, 2017

Sew Chaotically! - Kimono Sashiko Jacket - Lisette B6464 (A little late in posting...but better late than never!!!)

I planned to make a kimono jacket with Sashiko embroidery when I started on this top:

Annie Top by Tessuti
But which kimono jacket pattern to use!!!  I have enjoyed making several Lisette patterns:
This Blanket Coat

This dress....
and this jacket from her Passport pattern

And most recently, I used the pattern below for this little top in my Summer of Basics make-along! 
I figured this jacket included would be perfect!

After creating my stencil, I carefully traced it onto the cuff and neck band pieces.  Then, I decided exactly how I wanted to stitch the "flower" part of the design.  Consistency is important in having your Sashiko embroidery look its best.

I did all the long straight rows and came back around, stitching all the circles.
I made a straight 12.  The pattern comes together very easily.  I flat felled the side seams so the insides would have a clean finish. My only change was in construction. I sewed the cuff to the sleeve flat and then attached the sleeve flat, which allowed me to stitch the sleeve and sides in one go.  You turn up the cuff to the inside, so your seam is hidden. 
I am quite pleased with how it turned out.  The fabric is a linen blend, which is sort of the best of both you get a linen look with much easier care and without the wrinkles!  The only difficulty is that though the fabric seems like a simple navy on its's a little tricky when you pair it with other blues!  I made it as summer was waning, so it has seen limited use this fall with the cooler temps.  I can't wait to put it in serious wardrobe rotation in the spring!

Then, it struck me that this jacket would be cozy in fleece!
So I made one for my dear sweet Danita!

She's been with me...
through highs and lows!!

And because I had extra fabric...  What the heck?  Another for me!
Sew Chaotically! - les

Thursday, November 23, 2017

ISF35 - the viral vector for a CD40 agonist - as use as an intratumoral/intralesional melanoma treatment!!!

On the subject of intratumoral treatment of melanoma - drugs that are injected directly into the tumor, as the prior post on IMO-2125, a TLR agonist discussed, along with ALL these other intralesional/intratumoral therapies covered here:  ASCO 2017: All things intralesional/intratumoral
 - we've learned a couple of things:

1.  These drugs can have significant "by-stander" effect.  Meaning - they can kill not only the tumor they are injected it...but others...distant from the site of the injected tumor.

2.  As many melanoma experts said years ago, they will most likely turn out to be most effective when paired with systemic immunotherapy (as most of the research that is on-going is doing currently.

But...there's another one on the horizon.  It's been a long time in coming.  I posted this back in 2014:

CD40 Antibody therapy for melanoma....another way to activate the immune system?

And now, there's this:

Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain. Singh, Vianden, Cantwell, et al. Nat Commun. 2017 Nov 13.

CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8+ T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8+ T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8+ T cells, and an increased ratio of intratumoral CD8+ T cells to CD4+ Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain.
A triple-decker approach!!!  I like it!!  Now where is the slick MD Anderson poster boards for this one?????

Fingers crossed, ratties!  Fingers crossed. - c

Wednesday, November 22, 2017

Sew Chaotically!! - African Wax Print top for a beautiful friend!!!

I had so much fun with my first foray into the use of African Wax Prints!!!

Here's the whole story:  Sew Chaotically! - African Wax Print Butterfly dress!!!
My dear friend, Ashia, has always been hugely and sweetly supportive of my sewing efforts!  But you should have seen her face light up in admiration of this fabric in particular!!  Despite my wild abandon in cutting out the pieces of my dress with zero focus on conservation of fabric....thinking only of which swath of color I wanted to place where...and the fullness of the dress itself..... I STILL had loads of fabric left.  6 yards is a lot, y'all!!!  So, I took it into my head to make a top for her.  I had her loan me a simple sleeveless, tunic top that she liked and fit her well.  I started with a basic paper tracing of front and back, with a line for the bust dart.  I don't know what I was thinking...something along the lines of:  just cut that line and slip in extra space....but quickly discovered what those with a brain more spatially related than mine would have intuitively grasped!  That WON'T work!!! was onto the internet to learn how to do a full bust adjustment!!!  (If you have looked at this blog for half a minute, you KNOW that is something for which I have had no prior need!!!!)  If you ARE in need, these two links were really helpful:

Workroom Social: Full bust adjustment tutorial

Craftsy: Full bust adjustment

It seems pretty clear and straightforward...NOW....but it pinched my brain for a minute there!!!

And there she is!!!  The top and my beautiful friend!!!  Love you, Ashia!!! - les

Monday, November 20, 2017

IMO-2125, a TLR agonist combined with Yervoy (ipi) for folks with melanoma refractory to anti-PD-1

So, one of the MRF peeps put up a bit of an ad for this treatment...not entirely sure why, as that is not usually their role.  Perhaps they were just letting folks looking for a treatment option after failing anti-PD-1 know this trial was enrolling.  But, with so little intel out about this study and so many other options available - it piqued my interest.  It was quickly apparent that it is hard to find much info on it other than the super slick "presentations" made by the company who makes it, Idera, and the company who wants you to join their trial, MD Anderson, like these:

A Phase 1/2 trial of intratumoral (i.t.) IMO-2125 (IMO) in combination with checkpoint inhibitors (CPI) in PD-(L)1-refractory melanoma - out of MD Anderson

Idera Press Release for investors

But, when my intrepid medical researcher, partner in crime and all things got on the case, he found this:  Melanoma News Today - report from April 2017

It reads as follows:

Combining IMO-2125 and Yervoy Shows Promise in Certain Metastatic Melanoma Patients   By:  Daniela Semedo, Melanoma News Today, April 2017.

Combining {Idera's] intratumoral IMO-2125 treatment with Yervoy (ipilimumab) may be a promising treatment approach for patients with metastatic melanoma who are refractory to anti-PD-1 therapies, according to preliminary data from a Phase 1/2 clinical trial.
We are very pleased with the progress to date in the Phase 1 dose escalation trial of IMO-2125 in combination with ipilimumab, and with the outcomes observed,” Joanna Horobin, Idera’s chief medical officer, said in a press release. (Possibly the one I noted above.)

IMO-2125 in combination with ipilimumab demonstrated preliminary evidence of meaningful clinical activity in this anti-PD-1 refractory metastatic melanoma patient population which represents a high unmet medical need,” she said.
All dose levels have been well tolerated and did not exacerbate the safety issues commonly observed with ipilimumab,” Horobin said. “Furthermore, data from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of the trial.”
IMO-2125, a toll-like receptor (TLR) agonist, is designed to activate cells from the innate immune system and induce the production of interferon — a potent activator of the immune system. Together, this is thought to lead to the infiltration of tumor-killing T-cells.
Because tumors have developed a method to impair T-cells from recognizing and attacking them, Idera believes that the drug could work in synergy with known and approved immune checkpoint inhibitors.
The open-label Phase 1/2 study (NCT02644967) was designed to assess the safety and preliminary effectiveness of intratumoral IMO-2125 in combination with the CTLA-4 inhibitor Yervoy or the PD-1 inhibitor Keytruda (pembrolizumab) in patients with metastatic melanoma who progressed after receiving anti-PD-1 therapies.  The study was set to be conducted in two parts: a dose-escalation portion (Phase 1) to evaluate safety and tolerability of multiple dose levels, and a Phase 2 expansion portion to assess efficacy.
While the Phase 1 dose escalation of IMO-2125 in combination with Keytruda is ongoing, the company has now announced that the Phase 1 part assessing IMO-2125 plus Yervoy has met the pre-specified futility assessment, meaning that the combination reached the established efficacy cut-off.
The company announced that all dose levels of IMO-2125 were well tolerated, and that the 8 mg dose level was established as the recommended Phase 2 dose.
Nine participants out of an expected 21 have enrolled in the Phase 2 portion of the trial assessing the objective response rate of IMO-2125 in combination with Yervoy. Data will be compared with historical controls treated with Yervoy alone.
Houston’s MD Anderson Cancer Center will continue to lead the study and will be joined by other clinical sites. Idera expects to have overall response rate (ORR) data early next year.
I am very encouraged by the tremendous progress that has been made to date to advance us to this important stage in IMO-2125’s development cycle,” said Vincent Milano, Idera’s CEO. “There is a very clear unmet medical need for those patients for whom current checkpoint inhibitor therapies are not providing adequate solutions.
We are incredibly focused on advancing this program as rapidly as possible for these patients, and we are also looking forward to exploring areas outside of melanoma in which intratumoral IMO-2125 may also serve an important role through its unique mechanism of action within the tumor microenvironment,” he said.
Idera also said it has started meeting with regulatory agencies about the best path to follow to register the combined treatment of IMO-2125 and Yervoy in patients with PD-1 refractory metastatic melanoma.
In addition, the company said the Phase 1 clinical trial evaluating the combined treatment of intratumoral IMO-2125 and Keytruda in PD-1 patients with refractory melanoma is enrolling as planned.  Moreover, a Phase 1 clinical trial evaluating intratumoral IMO-2125 alone (NCT03052205) in multiple tumor types should be enrolling the first patient in coming months.
Hmmm.....  Well, it is certainly a fact that we have folks who fail to gain effective control of their melanoma with anti-PD-1 and it's 40% response rate, leaving them in desperate need of an effective therapy!  It is also true that I encourage and fully support looking at any and all possible treatments to help them.  Yet, I remain a little puzzled here.  This statement sounds strong, but is substantially lacking in, hmmm....what's the word??????  " from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of the trial.”  Oh!  I know what it is....DATA!!!!!!!!!!!!!!!  This report tells us NOTHING about how the folks in the phase 1 trial are doing!!!

An interesting aside:  The name TLR, toll-like receptor, came from the appearance the fruit fly larvae developed when used as subjects by researchers to isolate the molecule's function.  The larvae in whom the receptor was changed, looked very peculiar, or "droll", according to the German researchers who won a Nobel prize in medicine for this work.  And the German word for "droll" (i.e. funny) is "toll"!  The more you know....

While I hope IMO-2125 will absolutely be the cure for ever so many cancers, including melanoma, we need to remember that current intratumoral/intralesional therapies that are being combined with immunotherapy daily, to good effect, are available for melanoma patients in need and come WITH data supporting their efficacy!  Here's a post reviewing a wide variety of them and the DATA required for them to sally forth:

ASCO 2017: All things intralesional/intratumoral

If TLR agonists become the next great thing....will we all be cured of our melanoma AND have a great sense of humor...or just look a little funny?????  Hang tough ratties!  The road is long with lots of tolls!  And I mean LOTS!!! - c

Sunday, November 19, 2017

Back to the cooties in our guts....again!!!

We all want a magical cure for our melanoma!!  Short of that, we certainly want to do whatever we can to make sure the treatments we do utilize work to their very best effect!  In that vein, various studies have looked at the bacteria in our intestines, our 'microbiome' (or...the cooties in our gut!!), and how they may interact with immunotherapy.  Here is a prior post with links to several studies:

ASCO 2017: Melanoma, anti-PD1 and the microbes in your gut

Now there's this: 

Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Gopalakrishnan, Spencer, Nezi, et al.  Science. 2017 Nov 2. 

Pre-clinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-PD-1 immunotherapy (n=112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders (R) versus non-responders (NR). Analysis of patient fecal microbiome samples (n=43, 30R, 13NR) showed significantly higher alpha diversity and relative abundance of Ruminococcaceae bacteria in responding patients. Metagenomic studies revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and anti-tumor immunity in responding patients with a favorable gut microbiome, as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

Best I can tell you is what I've said before ~ it is likely that our best bet is to avoid antibiotics unless really needed, eat kimchi, sauerkraut, yogurt and kefir!  Or.....fecal transplant, anyone???! 

Yum!!! - c